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WO2002009865A1 - Production de capsules de polyelectrolyte par precipitation superficielle - Google Patents

Production de capsules de polyelectrolyte par precipitation superficielle Download PDF

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Publication number
WO2002009865A1
WO2002009865A1 PCT/EP2001/008909 EP0108909W WO0209865A1 WO 2002009865 A1 WO2002009865 A1 WO 2002009865A1 EP 0108909 W EP0108909 W EP 0108909W WO 0209865 A1 WO0209865 A1 WO 0209865A1
Authority
WO
WIPO (PCT)
Prior art keywords
particles
shell
template
template particles
polyelectrolyte
Prior art date
Application number
PCT/EP2001/008909
Other languages
German (de)
English (en)
Inventor
Andreas Voigt
Gleb Sukhorukov
Igor Radtchenko
Alexei Antipov
Edwin Donath
Helmuth MÖHWALD
Original Assignee
MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from DE2000137707 external-priority patent/DE10037707A1/de
Priority claimed from DE2000150382 external-priority patent/DE10050382A1/de
Application filed by MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. filed Critical MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V.
Priority to US10/343,670 priority Critical patent/US7056554B2/en
Priority to DE50103245T priority patent/DE50103245D1/de
Priority to CA002417792A priority patent/CA2417792C/fr
Priority to DK01969563T priority patent/DK1305109T3/da
Priority to AT01969563T priority patent/ATE273067T1/de
Priority to JP2002515408A priority patent/JP2004504931A/ja
Priority to EP01969563A priority patent/EP1305109B1/fr
Publication of WO2002009865A1 publication Critical patent/WO2002009865A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5192—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5089—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5138—Organic macromolecular compounds; Dendrimers obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/06—Making microcapsules or microballoons by phase separation
    • B01J13/10—Complex coacervation, i.e. interaction of oppositely charged particles
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
    • B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
    • B01J13/02—Making microcapsules or microballoons
    • B01J13/20—After-treatment of capsule walls, e.g. hardening
    • B01J13/22—Coating
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T428/00—Stock material or miscellaneous articles
    • Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
    • Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
    • Y10T428/2984—Microcapsule with fluid core [includes liposome]

Definitions

  • the invention relates to a method for producing nano or microcapsules, which comprise a polyelectrolyte shell, by surface precipitation from the solution.
  • capsules with a defined and small shell thickness and with selectively controllable permeability properties can be obtained.
  • Different types of covers e.g. Polyelectrolyte shells, polyelectrolyte / ion shells, but also shells made of uncharged polymers can be produced.
  • salts dissolved in the liquid contribute significantly to the stability of the shells formed by precipitation.
  • suitable salts are all water-soluble, low molecular weight salts, including inorganic salts such as chlorides, bromides, nitrates, sulfates and carbonates, which are mono- and polyvalent
  • Alkali, alkaline earth metals or transition metals such as iron, silver, copper.
  • Concentrations are preferably in the range of 0.5 mM to 1 M or higher in cases where the effect of the salt is to reduce the electrostatic interactions between the polyelectrolytes on the one hand and the polyelectrolytes and the template surfaces on the other hand.
  • the concentrations of the salts are preferably in the range of
  • the encapsulation method according to the invention enables the encapsulation of any colloidal particles.
  • liquid particles for example emulsified oil droplets or liquid-crystalline particles, or gaseous particles, for example air or other gas bubbles, can also be coated.
  • the size of liquid or gas particles to be encapsulated can be adjusted, for example, by adding surface-active substances to the liquid phase.
  • any colloidal solids in particular inorganic materials, e.g. Metals, ceramics, oxides or salt crystals, organic materials such as polymer latexes, organic precipitates, solidified oil droplets, gels or crystals, melamine formaldehyde particles, lipid vesicles, biological template particles such as cells or pollen are used.
  • the size of the template particles can reach up to 50 ⁇ m - especially when using biological template materials.
  • the size of the template particles is preferably up to 10 ⁇ m, particularly preferably from 5 nm to 10 ⁇ m and most preferably from 5 nm to 5 ⁇ m.
  • the shape of the template particles is not critical. Both spherical and anisotropic particles can be coated.
  • template particles are encapsulated which contain an active ingredient, for example themselves being an active ingredient.
  • This active ingredient can be selected, for example, from catalysts, in particular enzymes, for example enzyme crystals, nanoparticles, for example magnetic nanoparticles, biological macromolecules, etc., pharmaceutical active ingredients, sensor molecules, for example radioactive or non-radioactive labeling molecules such as fluorescent labels, crystals, polymers and gases.
  • the active substance particles can be added to the liquid phase or can be generated therein by precipitation. The precipitation can take place before or / and during the capsule formation and lead to crystals and / or amorphous structures.
  • the capsules can be used for introducing organic liquids such as alcohols or hydrocarbons, for example hexanol, octanol, octane or decane, or for encapsulating gases for ultrasound contrast media.
  • organic liquids such as alcohols or hydrocarbons, for example hexanol, octanol, octane or decane
  • Such capsules filled with an organic, water-immiscible liquid can also be used for chemical reactions, for example polymerization reactions.
  • the monomer can be specifically enriched in the interior of the capsules via its distribution equilibrium. If necessary, the monomer solution can be encapsulated in the interior prior to the start of the synthesis.
  • the active substance to be enclosed is coupled or immobilized on the template particle or encapsulated or absorbed by the template particle, e.g. by phagocytosis or endocytosis in living cells or by encapsulation of nanoparticles in soluble template materials. After disintegration of the template particles, the active ingredient is released into the interior of the polyelectrolyte shell.
  • the conditions for the disintegration of the template particle are expediently chosen so that no undesired decomposition of the active substance occurs.
  • the active substance can be coupled to the template directly, but can also be effected by a binding agent.
  • Molecules that can be degraded or degraded under certain conditions are preferably used as binding agents.
  • Polylactic acid is particularly preferably used as a binding agent.
  • the active ingredient is immobilized on the template particle, for example a partially crosslinked melamine formaldehyde particle, by means of the binding agent, in particular polylactic acid.
  • the active ingredient to be enclosed itself becomes part of the layer structure when coating the core.
  • the Active ingredient released inside the shell can be enclosed in the shell, in particular nanoparticles and non-biological macromolecular components and preferably biological macromolecules, such as proteins, in particular enzymes.
  • 4-pyrene sulfate (4-PS) cationic polymers or particles are fixed in the shell. By dissolving 4-PS in salt solutions, these particles are then released into the interior of the shell.
  • the incorporation of active substances into the interior enclosed by the shells can be carried out by introducing the active substances into the template particles beforehand when using reversible microgels as template particles.
  • the use of partially cross-linked methylol melamine cores before coating enables substances to be incorporated into swollen cores which are included in the core after reversible shrinkage.
  • soluble particles can be used as template particles. These soluble particles can be at least partially disintegrated without destroying the shell formed by precipitation through the particles.
  • soluble particles are partially crosslinked melamine formaldehyde particles, which can be adjusted to an acidic value, for example by adjusting the pH in the medium containing the coated particles ⁇ 1, 5, can be resolved while the cladding layer itself remains at least partially intact.
  • Partially crosslinked melamine formaldehyde particles can also be dissolved by chemical reactions, in particular by sulfonation in aqueous media. The production of such partially crosslinked melamine formaldehyde particles is described in detail in WO 99/47252.
  • dissolvable template particles are soluble polymer cores, for example urea Formaldehyde particles or salt crystals, or salt crystals, for example carbonate compounds whose aqueous solubility is controllable, or organic compounds which are not soluble in water but in ethanol, for example cyanine dyes.
  • soluble polymer cores for example urea Formaldehyde particles or salt crystals, or salt crystals, for example carbonate compounds whose aqueous solubility is controllable, or organic compounds which are not soluble in water but in ethanol, for example cyanine dyes.
  • cells e.g. eukaryotic cells, such as mammalian erythrocytes or plant cells, unicellular organisms such as yeast, bacterial cells such as E.coli cells, cell aggregates, subcellular particles such as cell organelles, pollen, membrane preparations or cell nuclei or hollow cell wall or pollen wall preparations produced by chemical and / or biological processes , Virus particles and aggregates of biomolecules, e.g. Protein aggregates such as immune complexes, condensed nucleic acids, ligand-receptor complexes etc. can be used.
  • the method according to the invention is also suitable for encapsulating living biological cells and organisms. Aggregates of amphiphilic materials, in particular membrane structures such as vesicles, e.g. Liposomes or micelles as well as other lipid aggregates.
  • Biological template particles can be disintegrated by adding lysis reagents.
  • Lysis reagents that can dissolve biological materials such as proteins and / or lipids are suitable.
  • the lysis reagents preferably contain a deproteinizing agent, for example peroxo compounds such as H 2 O 2 or / and hypochlorite compounds such as sodium or potassium hypochlorite.
  • the template particles are disintegrated within a short incubation period, for example from 1 min to 1 h at room temperature. The disintegration of the template particles is largely complete, since even when the remaining shells are viewed by electron microscopy, no residues of the particles can be detected.
  • capsules with partially dissolved shells can be produced.
  • the fragments formed during the disintegration of the template particles can escape from the interior of the capsules through pores, in particular nanopores, of the shell wall. Then, if desired, they can be separated from the capsules. This separation can be carried out by methods known to the person skilled in the art, for example by dialysis, filtration, centrifugation or / and controlled phase separation. However, it is often not necessary to separate template particle fragments.
  • the capsules can also be used without a separation step.
  • liquid or gaseous template particles can also be used, e.g. Drops of a micro or mini emulsion or gas bubbles of the appropriate size. Oil droplets which can be emulsified by ultrasound in an aqueous saline solution are particularly preferably used as the liquid template particles. The size of the liquid droplets or gas bubbles can be determined by appropriate measures, e.g. Set the power and duration of an ultrasound treatment to the desired sizes.
  • liquid active ingredients such as perfume oils, pharmaceutically active oils, lipophilic solid active ingredients dissolved in oils or gas bubbles can be encapsulated as contrast agents.
  • the interior can be loaded with molecules by varying the permeability of the HüMe as a function of the external physical and chemical parameters. A state of high permeability is set for loading. The enclosed material is then retained by changing the external parameters and / or closing the pores, for example by condensation of the shell or chemical and / or thermal modification of the pores or channels.
  • the precipitation method according to the invention permits the deposition of charged and / or uncharged components on the template particle.
  • the components required to form the shell contain at least one polyelectrolyte, for example two oppositely charged polyelectrolytes or / and a polyvalent metal cation and a negatively charged polyelectrolyte.
  • Polyelectrolytes are generally understood to mean polymers with ionically dissociable groups which can be part or a substituent of the polymer chain.
  • the number of these ionically dissociable groups in polyelectrolytes is usually so large that the polymers in the dissociated form (also called polyions) are water-soluble.
  • the term polyelectrolytes is also understood to mean ionomers in which the concentration of the ionic groups is not sufficient for solubility in water, but which have sufficient charges in order to undergo self-assembly.
  • the shell preferably comprises “real” polyelectrolytes.
  • polyelectrolytes are divided into polyacids and polybases. Polyanions are formed from polyacids during dissociation with the elimination of protons, which can be both inorganic and organic polymers.
  • Polybases contain groups that are capable of protons, e.g. by reaction with acids with salt formation. Polybases can have chain or lateral dissociable groups and form polycations by taking up protons.
  • Polyelectrolytes suitable according to the invention are both biopolymers, such as alginic acid, gum arabic, nucleic acids, pectins, proteins and others, and chemically modified biopolymers, such as ionic or ionizable polysaccharides, for example carboxymethyl cellulose, chitosan and chitosan sulfate, lignin sulfonates and synthetic polymers, such as Polymethacrylic acid, polyvinylsulfonic acid, polyvinylphosphonic acid and polyethyleneimine.
  • biopolymers such as alginic acid, gum arabic, nucleic acids, pectins, proteins and others
  • chemically modified biopolymers such as ionic or ionizable polysaccharides, for example carboxymethyl cellulose, chitosan and chitosan sulfate, lignin sulfonates and synthetic polymers, such as Polymethacrylic acid, polyvinyl
  • Suitable polyanions include naturally occurring polyanions and synthetic polyanions.
  • naturally occurring polyanions are alginate, carboxymethylamylose, carboxymethylcellulose, carboxymethyldextran, carageenan, cellulose sulfate, chondroitin sulfate, chitosan sulfate, dextran sulfate, gum arabic, gum guar, gum gellan, heparin, hyaluronic acid and pectin, a xant corresponding pH value.
  • Examples of synthetic polyanions are polyacrylates (salts of polyacrylic acid), anions of polyamino acids and their copolymers, polymaleinate, polymethacrylate, polystyrene sulfate, polystyrene sulfonate, polyvinyl phosphate, polyvinyl phosphonate, polyvinyl sulfate, polyacrylamide methyl propane sulfonate, polyl actate (malate), poly (butadiene), poly (butad) ethylene / maleinate), poly (ethacrylate / acrylate) and poly (glycerol methacrylate).
  • Suitable polybases include naturally occurring polycations and synthetic polycations.
  • suitable naturally occurring polycations are chitosan, modified dextrans, for example diethylaminoethyl-modified dextrans, hydroxymethylcellulose trimethylamine, lysozyme, polylysine, protamine sulfate, hydroxyethylcellulose trimethylamine and proteins at the corresponding pH.
  • Examples of synthetic polycations are polyallylamine, polyallylamine hydrochloride, polyamines, Polyvinylbenzyl- trimethyl ammonium chloride, polybrene, polydiallyldimethylammonium chloride, polyethyleneimine, polyimidazoline, polyvinylamine, polyvinylpyridine, poly (acrylamide / methacryloxypropyltrimethylammoniumbromid), poly (diallyldimethylammonium chloride / N-lisopropylacrylamid), poly (dimethylaminoethyl - acrylate / acrylamide), polydimethylaminoethyl methacrylate, polydimethylamino-epichlorohydrin, polyethyleneiminoepichlorohydrin, polymethacryloxyethyltrimethylammonium bromide, hydroxypropylmethacryloxyethyldimethylammonium chloride, poly (methyldiethylaminoethyl meth
  • Linear or branched polyelectrolytes can be used.
  • the use of branched polyelectrolytes leads to less compact polyelectrolyte multi-films with a higher degree of wall porosity.
  • polyelectrolyte molecules can be crosslinked within or / and between the individual layers, e.g. by crosslinking amino groups with aldehydes.
  • Amphiphilic polyelectrolytes e.g. Amphiphiie block or random copolymers with partial polyelectrolyte character to reduce permeability to polar small molecules are used.
  • amphiphilic copolymers consist of units of different functionality, e.g.
  • the capsule walls can be controlled in terms of their permeability or other properties.
  • Weak polyelectrolytes, polyampholytes or copolymers with a poly (N-isopropyl-acrylamide) component e.g. Poly (N-isopropylacrylamide-acrylic acid), which change their water solubility as a function of temperature via the equilibrium of hydrogen bonds, which is associated with swelling.
  • degradable polyelectrolytes for example photo-, acid-, base-, salt- or thermolabile polyelectrolytes
  • the release of enclosed active substances can be controlled by dissolving the capsule walls.
  • conductive polyelectrolytes or polyelectrolytes with optically active groups can also be used as capsule components for certain possible applications.
  • suitable choice of the polyelectrolytes it is possible to set the properties and composition of the polyelectrolyte shell of the capsules according to the invention in a defined manner. The composition of the shells can be varied within wide limits by the choice of substances in the layer structure.
  • polyelectrolytes or ionomers there are no restrictions with regard to the polyelectrolytes or ionomers to be used, as long as the molecules used have a sufficiently high charge and / or have the ability to bind to the via other types of interaction, such as hydrogen bonds and / or hydrophobic interactions layer below.
  • Suitable polyelectrolytes are thus both low molecular weight polyelectrolytes or polyions and macromolecular polyelectrolytes, for example polyelectrolytes of biological origin.
  • the permeability of the envelope wall is of particular importance for the use of the capsules.
  • the large number of available polyelectrolytes enables the production of a large number of shell compositions with different properties.
  • the electrical charge of the outer shell can be adapted to the application.
  • the inner shell can be adapted to encapsulated active ingredients, which means e.g. stabilization of the active ingredient can be achieved.
  • the permeability of the shell wall can also be influenced by the choice of the polyelectrolytes in the shell and by the wall thickness and the ambient conditions. This allows a selective design of the permeability properties as well as a defined change in these properties.
  • the permeability properties of the shell can be further modified by pores in at least one of the polyelectrolyte layers. With a suitable choice, such pores can be formed by the polyelectrolytes themselves. In addition to the polyelectrolytes, the shell can also do other things Include substances to achieve a desired permeability. In particular, the introduction of nanoparticles with anionic and / or cationic groups or of surface-active substances, such as surfactants and / or lipids, can reduce the permeability for polar components.
  • selective transport systems, such as carriers or channels, in the polyelectrolyte shell, in particular in lipid layers enables the transverse transport properties of the shell to be precisely adapted to the particular application.
  • the pores or channels of the envelope wall can be opened or closed in a targeted manner by chemical modification and / or change in the ambient conditions. For example, a high salt concentration of the surrounding medium leads to a high permeability of the envelope wall.
  • a first embodiment of the method according to the invention comprises a complex precipitation or coacervation of two oppositely charged polyelectrolytes from alkaline solution, in which both are kept in solution simultaneously without reacting with one another.
  • the template particles to be coated are added to this solution.
  • acid e.g. HCl titrated to the neutral range, whereby the template particles are encapsulated.
  • the template particles can optionally be dissolved by filtration, centrifugation or sedimentation.
  • the surface precipitation can be carried out from a solution comprising a complex of a low molecular weight ion and an oppositely charged polyelectrolyte.
  • suitable low-molecular ions are metal cations, inorganic anions such as sulfate, carbonate, phosphate, nitrate etc., charged surfactants, charged lipids and charged oligomers in combination with a correspondingly oppositely charged polyelectrolyte. trolyten. This creates a distributed source for one polyelectrolyte in the presence of the other polyelectrolyte.
  • the polyelectrolyte of the complex can be both the polycation and the polyanion.
  • a positively charged polyelectrolyte with a multiply negatively charged low-molecular anion for example sulfate
  • a coating of the template particles taking place.
  • the coated template particles can be separated from the free complexes, for example by centrifugation, filtration and subsequent washing, and - if the particles are soluble - can be dissolved to produce microcapsules.
  • Yet another preferred embodiment comprises surface precipitation from a solution containing partially destabilized polyelectrolyte complexes (polycation / polyanion) by means of salt addition or / and pH variation.
  • polycation / polyanion partially destabilized polyelectrolyte complexes
  • the negatively and positively charged polyelectrolyte can be dissolved in an aqueous solution with a high salt content, preferably a salt content of> 0.5 mol / l, e.g. 1 M NaCl, introduced and stirred.
  • After adding the template particles they are coated.
  • the coated template particles can be obtained, for example, by centrifugation or filtration and subsequent washing and, if appropriate, dissolved to produce microcapsules.
  • the shell comprises metal cations and at least one negatively charged polyelectrolyte.
  • Divalent metal cations and in particular trivalent metal cations are used as metal cations, for example.
  • suitable metal cations are alkaline earth metal cations, transition metal cations and rare earth element cations such as Ca 2+ , Mg 2+ , Y 3 + , Tb 3+ and Fe 3 + .
  • monovalent cations such as Ag + can also be used.
  • the components required to form the shell comprise at least one macromolecule, e.g. an abiogenic macromolecule, such as an organic polymer, or a biomolecule, such as a nucleic acid, e.g. DNA, RNA or a nucleic acid analog, a polypeptide, a glycoprotein or a polysaccharide with a molecular weight of preferably> 5 kD, and particularly preferably> 10 kD.
  • the macromolecules can carry charges, e.g. such as nucleic acids or else uncharged, such as polysaccharides, e.g. Dextran.
  • the macromolecules can optionally be combined with polyelectrolytes and / or polyvalent metal cations, e.g. Combinations of macromolecular and low molecular weight biological cell substances, macromolecular and low molecular weight abiogenic substances and macromolecular and biogenic and abiogenic substances can be used.
  • the components specified for forming the shell comprise a mixture of a plurality of polyelectrolytes or / and lipids or / and proteins or / and peptides or / and nucleic acids or / and further organic and inorganic compounds of biogenic or abiogenic origin.
  • a suitable composition of the solvent with regard to salt content, pH value, co-solvents, surfactants and by a suitable choice of coating conditions, eg temperature, rheological conditions, presence of electrical and / or magnetic fields, presence of light the various shell components become for self-assembly on the templates, creating complex structures with diverse biomimetic properties.
  • Yet another preferred embodiment of the method is characterized in that the bringing together of the liquid saline shell phase with the templates changes the system conditions in such a way that without further external stimulation, with the exception of permanent mixing, the casings are built up spontaneously, which, if necessary, can be dissolved the template remains intact.
  • the precipitation according to step (b) of the method according to the invention takes place under conditions such that a shell with a defined thickness in the range from 1 to 100 nm, preferably 1 to 50 nm, particularly preferably 5 to 30 nm and most preferably 10 to 20, around the template nm is formed.
  • the wall thickness and the homogeneity of the capsule shell are determined by the rate of polymer precipitation. This essentially depends on the concentration of the template particles, the concentration of the coating components and the speed of the solubility change in the liquid phase causing the precipitation.
  • the precipitation can take place, for example, by introducing part of the components forming the shell in the liquid phase and then adding one or more further shell components.
  • a precipitation step can be used, for example, for a combination of metal cations and oppositely charged polyelectrolytes.
  • Another possibility of precipitation consists in that the components required for the formation of the shell are already completely in the liquid phase and that the liquid phase causes the precipitation.
  • This change in the liquid phase can include, for example, a change in the pH and / or a change in the composition of the liquid phase, for example by adding a solvent component and / or removing a solvent component.
  • precipitation of hydrophilic biopolymers such as DNA or polysaccharides can be effected by adding ethanol to an aqueous liquid phase, while the precipitation of Polyelectrolyte combinations by evaporation of an organic solvent, such as acetone from the liquid phase.
  • the coating method according to the invention can comprise carrying out at least one additional coating step before or / and after the precipitation step.
  • Such an additional coating step can include, for example, the application of one or more lipid layers or / and the layer-by-layer application of polyelectrolytes.
  • a modification of the permeability of a shell can be achieved by depositing lipid layers and / or amphiphilic polyelectrolytes on the polyelectrolyte shell. In this way, the permeability of the shells for small and polar molecules can be greatly reduced.
  • lipids that can be deposited on the shells are lipids that carry at least one ionic or ionizable group, e.g. Phospholipids such as dipalmitoylphosphatidic acid or zwitterionic phospholipids such as dipalmitoylphosphatidylcholine or also fatty acids or corresponding long-chain alkylsulfonic acids.
  • Phospholipids such as dipalmitoylphosphatidic acid
  • zwitterionic phospholipids such as dipalmitoylphosphatidylcholine or also fatty acids or corresponding long-chain alkylsulfonic acids.
  • lipid multilayers can be deposited on the shell.
  • Polyelectrolytes can be applied in layers, for example as described in WO 99/47252.
  • the layered shell structure can be combined, for example, with the precipitation step according to the invention in such a way that a small layer, for example 1 to 4 layers, of polyelectrolytes is first built up on the template particle, followed by a precipitation step according to the invention.
  • a layer-by-layer deposition of polyelectrolytes on the shell can also take place after the precipitation steps.
  • Monodisperse capsules can be produced by the method according to the invention. It is thus possible to obtain a composition with a capsule distribution in which the proportion of capsules whose deviation from the mean diameter is> 50% is less than 20%, preferably less than 10% and particularly preferably less than 1%.
  • the capsules are very stable against chemical, biological, mechanical and thermal loads.
  • the capsules can optionally be dried, frozen or / and freeze-dried with included active ingredients without impairing their properties. After thawing or resuspending in a solvent, e.g. aqueous solution, intact capsules are obtained under suitable media conditions and / or with an appropriate media composition.
  • a solvent e.g. aqueous solution
  • a powdery composition is obtained which can be resuspended in suitable solvents, in particular in aqueous solutions. Drying can be carried out by known methods, in particular at elevated or reduced temperature and / or reduced pressure.
  • FIG. 1 shows an embodiment of the method according to the invention comprising the one-step formation of a polyelectrolyte / ion shell on colloidal template particles.
  • FIG. 2 shows a further embodiment of the method according to the invention, comprising self-assembly of polymer films on the surface of colloidal particles.
  • FIG. 3 shows a scanning microscopic confocal laser image of microcapsules, produced by a one-step precipitation from the temporary mixture water / acetone / sodium bromide with PSS 500 and PBVTAC.
  • the template was a dissolvable melamine formaldehyde latex particle with a diameter of 5.2 ⁇ m.
  • the solution window was left by evaporation of acetone.
  • FIG. 4 shows a scanning microscopic confocal laser image of microcapsules, obtained by a one-step process from the temporary mixture of water / acetone / sodium bromide with PSS 500 and PVBTAC.
  • the template was a dissolvable 5.2 ⁇ m diameter melamine formaldehyde latex particle.
  • the solution window was left by adding water.
  • Figure 5 shows a confocal microscopic image of colloidal
  • Figure 6 shows a microscopic confocal image of colloidal particles coated by precipitates of fluorescently labeled dextran (a) and fluorescently labeled DNA (b) on melamine formaldehyde particles by dropwise addition of ethanol to an aqueous suspension.
  • FIG. 7 shows empty shells made of the polyanion / metal complex PSS / Tb, characterized by atomic force microscopy.
  • FIG. 7a shows the top view of a capsule made of 20 cladding layers and
  • FIG. 7b shows the top view of several capsules each made up of about 100 cladding layers.
  • FIG. 1 shows a schematic representation of two embodiments of the method according to the invention.
  • a suspension of template particles (2) is produced which contains metal ions, for example ions of a polyvalent metal or ions of a noble metal, such as Ag + (4).
  • metal ions for example ions of a polyvalent metal or ions of a noble metal, such as Ag + (4).
  • an ion / polyelectrolyte shell is precipitated on the template particles.
  • the coated template particles (8) can be processed further in different ways. Empty capsules (10) can thus be produced by dissolving the template particles.
  • Metal-coated capsules (12) are obtained by reducing the metal ions.
  • capsules are produced with an anisotropic shell, the inner part being an ion / polyelectrolyte shell and the outer part being a layered polyelectrolyte / polyelectrolyte shell.
  • Empty capsules (18) can then be produced by dissolving the template particles.
  • the inner ion / polyelectrolyte part of the shell can be dissolved by removing the metal ions (4), so that the polymer (6) is encapsulated (20) inside the shell formed from the oppositely charged polyelectrolytes (14a, 14b).
  • FIG. 2 Another embodiment of the method according to the invention is shown in FIG. 2.
  • a suspension of colloidal template particles (32) is presented in a liquid phase, which contains a polymer, for example a nucleic acid, a protein, a polysaccharide or a synthetic polymer, in dissolved form.
  • a polymer for example a nucleic acid, a protein, a polysaccharide or a synthetic polymer, in dissolved form.
  • Layered deposition of oppositely charged polyelectrolytes produces coated template particles with an anisotropic shell (40), the inner section of the shell being formed by the precipitated polymer and the outer section being formed by layers of oppositely charged polyelectrolyte. If soluble template particles are used, these can be dissolved, a polymer (42) encapsulated in the polyelectrolyte / polyelectrolyte shell being formed.
  • Sodium polystyrene sulfate with a molecular weight of about 500,000 (PSS 500 ) and poly (vinylbenzyltrimethylammonium) chloride with a molecular weight of about 1 80,000 (PVBTAC) were purchased from Polysiences Europe GmbH.
  • Sodium polystyrene sulfate with a molecular weight of about 70,000 (PSS 70 ) and poly (allylamine hydrochloride) with a molecular weight of 50 to 65,000 (PAH) were purchased from Aldrich.
  • MF latex Partially crosslinked monodisperse meiamin-formaldehyde particles (MF latex) with diameters of 5.2 and 10 ⁇ m were obtained from Microparticles GmbH, Berlin, Germany. These particles are decomposable in acidic solutions of HCI (pH - 1), sodium pyrosulfite solutions or organic solvents.
  • SFM images were obtained using a Digital Instruments Nanoscope Purple.
  • the sample was prepared by applying a drop of the microcapsule suspension to a clean mica surface and drying in air. The dried microcapsules were examined in contact mode.
  • Microcapsules produced by layer-by-layer deposition according to the prior art showed a typical ultra-thin shell structure with a small wall thickness of approximately 15 nm. These microcapsules could be completely dissolved by adding the ternary mixture of water / acetone / sodium bromide.
  • FIGS. 3 and 4 CLSM images of capsules produced by the one-step surface precipitation according to the invention are shown in FIGS. 3 and 4.
  • the solution window was exited by acetone evaporation and in Figure 4 by adding water.
  • the size and shape of the microcapsules are similar to that of the template particles.
  • a large proportion of the microcapsules are slightly smaller than the original template particles.
  • An examination of the permeability properties showed that - as in the case of the step-by-step capsules - small polar dyes can penetrate the shell.
  • PSS with a molecular weight of 70,000, PAH with a molecular weight of 50,000 and acridine orange (AO) were obtained from Aldrich.
  • Y (NO 3 ) 3 , FeCI 3 and TbCI 3 were purchased from Merck.
  • Dipicolinic acid (DPA) and 4-pyrene sulfate (4-PS) were obtained from Molecular probes.
  • DNA and dextran (molecular weight 76,000) labeled with rhodamine (Rd) were purchased from Sigma.
  • Polystyrene latex particles (PS) modified with sulfate groups were, as in Furizava et al. (Kolloid-ZZPolym, 250 (1972), 908). Dispersions of acid-soluble melamine formaldehyde Hydparticles (MF latex) with diameters of 4 and 6.5 ⁇ m were obtained from Microparticels GmbH, Berlin, Germany.
  • Table 1 shows the data relating to the final concentration of MF particles, Tb 3 + ions and the concentration of PSS after addition to the suspension. Remarkably, about 80 to 85% of the PSS used was adsorbed on the MF latex particles at all the concentrations examined.
  • the MF particles were examined by confocal microscopy. A typical image for MF particles coated with PSS / Tb 3+ is shown in FIG. 5. The fluorescent label covers the MF particles evenly. Virtually no fluorescent label was found outside the particles. Table 1
  • the controlled precipitation of polymers onto the surface of colloidal particles was carried out by reducing the solubility of polymers.
  • DNA and dextran were used as polymers because of their low solubility in ethanol.
  • Typical fluorescence confocal microscope images are shown in FIGS. 6a and b. As can be seen from the pictures, the fluorescent marking on the particle surface is homogeneous. An estimate of the mean The thickness of the polymer film on the particle gives a value of approximately 50 monomolecular layers of DNA for DNA, ie a thickness of approximately 100 nm.
  • FIG. 7a shows a typical image (top view) of a capsule with 20 monomolecular Tb / PSS layers.
  • the spherical shape observed in solution by confocal microscopy changes to a more polygonal shape after drying.
  • the average minimum height of the capsules obtained from several measurements is approximately 20 nm.
  • FIG. 7b shows the top view of an SFM image of a sample with several capsules, consisting of approximately 100 monomolecular layers of Tb / PSS. A number of the capsules have broken. This lower stability is believed to be due to the increased thickness of the sheath, which reduces the permeability of the capsule. When the MF latex is dissolved, this leads to a higher osmotic pressure and thus to an easier breaking of the capsules.
  • Example 3 Complex precipitation or coacervation from alkaline solution of PSS and PAH.
  • a starting solution of the two polyelectrolytes was prepared, in which both are kept in solution simultaneously without reacting with one another (similar to the ternary solvent). This was achieved by presenting 10 ml of 0.1% (w / w) NaOH solution with 0.1 M NaCl. 15 mg of PSS (70,000 MW) and 10 mg of PAH (50,000 to 65,000 MW) were dissolved in this solution in succession. It was shaken until completely dissolved (approx. 15 minutes). This solution is then stable for several hours. 1 ml of melamine formaldehyde (MF) latex with a diameter of, for example, 4.7 ⁇ m was added.
  • MF melamine formaldehyde
  • a starting solution of the two polyelectrolytes is prepared, in which both are in solution simultaneously without reacting with one another. This is achieved by presenting 100 ml of 0.1% (w / w) NaOH solution with 0.1 M NaCl. 300 mg of PSS (70,000 MW) and 200 mg of PAH (50-65,000 MW) are dissolved in this solution in succession. It is shaken until completely dissolved. This solution is stable for several hours. 20 ml of perfume oil are added. The Ultra-Turrax is then used for emulsification and then quickly tritrated with 10% (w / w) HCI to the neutral range. The emulsion is then cleaned, e.g. washed several times in the separating funnel. The result was an emulsion that was stable for months.
  • Example 5 Surface precipitation from a solution containing a complex of polyelectrolyte and low molecular weight ligand and the correspondingly oppositely charged polyelectrolyte Solution I: 0.5 ml PAH solution (MW 50,000-65,000, 1 mg / ml) with NaCl (0.01-100 mM) + 750 ul sodium sulfate solution (10 -2 M); Solution II: 0.5 ml PSS (MG 70,000, 5 mg / ml) + 10 l melamine formaldehyde template particles with a diameter of 6.1 ⁇ m. Solution II is added to solution I and touched.
  • PAH solution MW 50,000-65,000, 1 mg / ml
  • NaCl 0.01-100 mM
  • Solution II 0.5 ml PSS (MG 70,000, 5 mg / ml) + 10 l melamine formaldehyde template particles with a diameter of 6.1 ⁇ m.
  • Solution II is added to solution I and touched.
  • the system is cleaned (separation of the coated templates from the free complexes by centrifugation or filtration with subsequent washes).
  • the template particles are dissolved by transferring them into a HCl solution of pH 1 and the microcapsules are obtained by further cleaning steps.
  • Example 6 Surface precipitation from a solution containing partially destabilized polyelectrolyte complexes (polycation / polyanion) by adding salt and / or pH variation. 20 mg of PSS and 10 mg of PAH are introduced into 10 ml of 1 M NaCl. The system is stirred for 10 minutes. Then 1 ml of 4.7 ⁇ m MF latex is added. The system is stirred for several hours. It is then cleaned or washed by centrifugation or filtration and the templates are dissolved in dilute HCl (pH ⁇ 1) and the capsules are obtained.
  • Example 7 One-step precipitation from a solution containing a complex of a polyelectrolyte and a polyvalent ion
  • Solution I 1 ml of PSS solution (2 mg / ml) is mixed with 200 ⁇ l of a Y (NO 3 ) 3 solution (2 x 10 "2 M). The resulting charge ratio between sulfate and yttrium is 5: 3.
  • Solution II 400 ⁇ l of oil are mixed with 1 ml of water. The mixture is ultrasonically emulsified in an Ultra-Turrax for 3 to 4 minutes. Solution I is then quickly added to solution II and the resulting emulsion is vortexed for 2 minutes. The emulsion is stable for more than 20 hours and can optionally serve as a starting system for further coatings.
  • the method according to the invention is universally applicable.
  • the physico-chemical conditions of the medium are set in this way, e.g. due to the high salt content that the preformed or / and freshly formed polyelectrolyte complexes in the coating liquid are unstable. It then surprisingly turns out that the distribution of the polyelectrolytes over all involved compartments takes place in finite time, which can be controlled by suitable parameters. Of course, this also includes the particle / medium or oil / medium phase boundary.
  • the polyelectrolytes can arrange themselves in the known three-dimensional network structure with more or less water. By post-treatment, e.g. in aqueous solutions of high salt concentration, this can be transferred to other configurations. For example, an insufficiently networked shell can be converted into a more networked one.

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Abstract

L'invention concerne un procédé pour produire des nanocapsules ou des microcapsules, comprenant une enveloppe de polyélectrolyte, par précipitation superficielle à partir d'une solution et par application d'une enveloppe sur les particules de matrice. Ce procédé comprend les étapes suivantes : (a) mise à disposition d'une dispersion de particules de matrice de dimensions appropriées dans une phase liquide saline contenant les composants nécessaires à la formation de l'enveloppe, sous forme dissoute ; et (b) précipitation des composants à partir de la phase liquide sur les particules de matrice dans des conditions permettant la formation d'une enveloppe, présentant une épaisseur comprise entre 1 et 100 nm, autour des particules de matrice.
PCT/EP2001/008909 2000-08-02 2001-08-01 Production de capsules de polyelectrolyte par precipitation superficielle WO2002009865A1 (fr)

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US10/343,670 US7056554B2 (en) 2000-08-02 2001-08-01 Production of polyelectrolyte capsules by surface precipitation
DE50103245T DE50103245D1 (de) 2000-08-02 2001-08-01 Polyelektrolytkapselherstellung durch oberflächenpräzipitation
CA002417792A CA2417792C (fr) 2000-08-02 2001-08-01 Production de capsules de polyelectrolyte par precipitation superficielle
DK01969563T DK1305109T3 (da) 2000-08-02 2001-08-01 Fremstilling af polyelektrolytkapsler ved overfladepræcipitation
AT01969563T ATE273067T1 (de) 2000-08-02 2001-08-01 Polyelektrolytkapselherstellung durch oberflächenpräzipitation
JP2002515408A JP2004504931A (ja) 2000-08-02 2001-08-01 表面沈澱による高分子電解質カプセルの製造
EP01969563A EP1305109B1 (fr) 2000-08-02 2001-08-01 Production de capsules de polyelectrolyte par precipitation superficielle

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DE10037707.6 2000-08-02
DE2000137707 DE10037707A1 (de) 2000-08-02 2000-08-02 Polyelektrolytkapselherstellung durch Oberflächenpräzipitation
DE10050382.9 2000-10-11
DE2000150382 DE10050382A1 (de) 2000-10-11 2000-10-11 Verkapselung von Flüssigkeiten

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002017888A2 (fr) * 2000-08-28 2002-03-07 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Gestion et support de proprietes de liberation de capsules multicouches polyelectrolytiques
US7321022B2 (en) 2003-08-29 2008-01-22 Louisiana Tech University Foundation, Inc. Method for controlling stability of nanofabricated polypeptide multilayer films, coatings, and microcapsules
US7364585B2 (en) 2003-08-11 2008-04-29 Boston Scientific Scimed, Inc. Medical devices comprising drug-loaded capsules for localized drug delivery
WO2009016091A1 (fr) * 2007-08-01 2009-02-05 Unilever Plc Particules enrobées
US7544770B2 (en) 2003-08-29 2009-06-09 Louisiana Tech Foundation, Inc. Multilayer films, coatings, and microcapsules comprising polypeptides
US7550557B2 (en) 2003-08-29 2009-06-23 Louisiana Tech University Foundation, Inc. Multilayer films, coatings, and microcapsules comprising polypeptides
US7767219B2 (en) 2003-01-31 2010-08-03 Boston Scientific Scimed, Inc. Localized drug delivery using drug-loaded nanocapsules
US7829119B2 (en) * 2003-10-20 2010-11-09 William Marsh Rice University Method to fabricate microcapsules from polymers and charged nanoparticles
US8119153B2 (en) 2004-08-26 2012-02-21 Boston Scientific Scimed, Inc. Stents with drug eluting coatings
US8187583B2 (en) 2009-01-30 2012-05-29 Conopco, Inc. Oil-in-water emulsions

Families Citing this family (73)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7101575B2 (en) * 1998-03-19 2006-09-05 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly
US7640083B2 (en) 2002-11-22 2009-12-29 Monroe David A Record and playback system for aircraft
JP4944348B2 (ja) * 2000-09-08 2012-05-30 三栄源エフ・エフ・アイ株式会社 テトラフェニルバクテリオクロリン誘導体およびそれを含む組成物
DE10127526A1 (de) * 2001-05-31 2002-12-12 Novosom Ag Verfahren zur Herstellung und Auflösung von Nano- und Mikrokapseln
US20080026068A1 (en) * 2001-08-16 2008-01-31 Baxter Healthcare S.A. Pulmonary delivery of spherical insulin microparticles
DE10151290A1 (de) * 2001-10-22 2003-04-30 Roehm Gmbh Verfahren zur Herstellung von wirkstoffhaltigen Pellets
US6837171B1 (en) 2002-04-29 2005-01-04 Palmer/Snyder Furniture Company Lightweight table with unitized table top
US20030119203A1 (en) * 2001-12-24 2003-06-26 Kimberly-Clark Worldwide, Inc. Lateral flow assay devices and methods for conducting assays
US7504364B2 (en) * 2002-03-01 2009-03-17 Receptors Llc Methods of making arrays and artificial receptors
US7153754B2 (en) * 2002-08-29 2006-12-26 Micron Technology, Inc. Methods for forming porous insulators from “void” creating materials and structures and semiconductor devices including same
US20060057625A1 (en) * 2002-09-16 2006-03-16 Carlson Robert E Scaffold-based artificial receptors and methods
US7469076B2 (en) * 2003-09-03 2008-12-23 Receptors Llc Sensors employing combinatorial artificial receptors
US20050136483A1 (en) * 2003-09-03 2005-06-23 Receptors Llc Nanodevices employing combinatorial artificial receptors
US20040137481A1 (en) * 2002-09-16 2004-07-15 Receptors Llc Artificial receptor building blocks, components, and kits
US20050037381A1 (en) * 2002-09-16 2005-02-17 Receptors Llc Artificial receptors, building blocks, and methods
DE10244503A1 (de) * 2002-09-25 2004-04-08 Capsulution Nanoscience Ag Methode zur Herstellung und Stabilisierung von Mikro- und Nanosuspensionen mit Amphiphilen und Polyelektrolyten
DE10254636A1 (de) * 2002-11-22 2004-06-09 Capsulution Nanoscience Ag Verfahren zum Modifizieren von Mikropartikeln sowie Vorrichtung zum Modifizieren von Mikropartikeln
EP1613737A4 (fr) 2003-03-28 2008-12-03 Receptors Llc Recepteurs artificiels comprenant des blocs de construction immobilises de maniere reversible et procedes
DE10361084A1 (de) * 2003-06-13 2005-01-05 Henkel Kgaa Lagerstabile Bleichmittelzusammensetzungen auf Basis von Peroxycarbonsäuren
DE10361170A1 (de) * 2003-06-13 2005-01-05 Henkel Kgaa Lagerstabiles Polyelektrolytkapselsystem auf Basis von Peroxycarbonsäuren
DE10361100A1 (de) * 2003-06-13 2005-01-05 Henkel Kgaa Lagerstabile Kapseln auf Basis von Peroxycarbonsäuren
US7615530B2 (en) * 2003-08-29 2009-11-10 Artificial Cell Technologies, Inc. Immunogenic compositions and methods of use
US7943395B2 (en) 2003-11-21 2011-05-17 Kimberly-Clark Worldwide, Inc. Extension of the dynamic detection range of assay devices
US8137728B2 (en) * 2004-03-11 2012-03-20 University Of Massachusetts Biopolymer encapsulation and stabilization of lipid systems and methods for utilization thereof
DE102004013637A1 (de) * 2004-03-19 2005-10-13 Capsulution Nanoscience Ag Verfahren zur Herstellung von CS-Partikeln und Mikrokapseln unter Verwendung poröser Template sowie CS-Partikel und Mikrokapseln
US7744644B2 (en) * 2004-03-19 2010-06-29 Boston Scientific Scimed, Inc. Medical articles having regions with polyelectrolyte multilayer coatings for regulating drug release
US8728525B2 (en) * 2004-05-12 2014-05-20 Baxter International Inc. Protein microspheres retaining pharmacokinetic and pharmacodynamic properties
WO2005110592A1 (fr) * 2004-05-17 2005-11-24 Yki, Ytkemiska Institutet Ab Particules mesoporeuses chargees avec une substance active
US7758892B1 (en) * 2004-05-20 2010-07-20 Boston Scientific Scimed, Inc. Medical devices having multiple layers
WO2006028930A2 (fr) 2004-09-03 2006-03-16 Receptors Llc Recepteurs artificiels combinatoires contenant des elements constitutifs de liaison sur des squelettes
US7985715B2 (en) * 2004-09-11 2011-07-26 Receptors Llc Combinatorial artificial receptors including peptide building blocks
EP1808225B1 (fr) * 2004-10-18 2014-04-16 Seiko Epson Corporation Produit d'encapsulation, procédé servant à produire celui-ci et composition d'encre
DE502006005846D1 (de) 2005-04-13 2010-02-25 Abbott Gmbh & Co Kg Verfahren zur schonenden herstellung hochfeiner partikelsuspensionen und hochfeiner partikel sowie deren verwendung
EP1885335A1 (fr) * 2005-04-27 2008-02-13 BAXTER INTERNATIONAL INC. (a Delaware corporation) Microparticules a surface modifiee et procedes de formation et d'utilisation associes
JP4997408B2 (ja) * 2005-05-30 2012-08-08 独立行政法人産業技術総合研究所 中空状複合体及びその製造方法
US20070048383A1 (en) * 2005-08-25 2007-03-01 Helmus Michael N Self-assembled endovascular structures
ES2462519T3 (es) * 2005-10-25 2014-05-23 Artificial Cell Technologies, Inc. Composiciones inmunógenas y procedimientos de uso
US7914891B2 (en) 2005-12-28 2011-03-29 Kimberly-Clark Worldwide, Inc. Wipes including microencapsulated delivery vehicles and phase change materials
US7442439B2 (en) 2005-12-28 2008-10-28 Kimberly-Clark Worldwide, Inc. Microencapsulated heat delivery vehicles
US7497351B2 (en) 2006-05-30 2009-03-03 Kimberly-Clark Worldwide, Inc. Wet wipe dispensing system
US7654412B2 (en) 2006-05-30 2010-02-02 Kimberly-Clark Worldwide, Inc. Wet wipe dispensing system for dispensing warm wet wipes
US20070281031A1 (en) * 2006-06-01 2007-12-06 Guohan Yang Microparticles and methods for production thereof
WO2008005509A2 (fr) * 2006-07-06 2008-01-10 Massachusetts Institute Of Technology Procédés et compositions destinés à modifier des surfaces biologiques
US7964574B2 (en) * 2006-08-04 2011-06-21 Baxter International Inc. Microsphere-based composition for preventing and/or reversing new-onset autoimmune diabetes
JP2010505882A (ja) * 2006-10-06 2010-02-25 バクスター・インターナショナル・インコーポレイテッド 表面改質微粒子を含むマイクロエンカプセルならびに、その形成および使用の方法
US7517582B2 (en) 2006-12-14 2009-04-14 Kimberly-Clark Worldwide, Inc. Supersaturated solutions using crystallization enthalpy to impart temperature change to wet wipes
US8192841B2 (en) 2006-12-14 2012-06-05 Kimberly-Clark Worldwide, Inc. Microencapsulated delivery vehicle having an aqueous core
US20090043276A1 (en) * 2007-08-09 2009-02-12 Boston Scientific Scimed, Inc. Drug delivery device, compositions and methods relating thereto
US8431508B2 (en) * 2007-10-30 2013-04-30 Cerahelix, Inc. Inorganic structure for molecular separations
RU2530653C2 (ru) * 2008-01-24 2014-10-10 Юниверсити Оф Юта Рисерч Фаундейшн Адгезивные комплексные коацерваты и способы их получения и применения
US8283384B2 (en) 2008-01-24 2012-10-09 University Of Utah Research Foundation Adhesive complex coacervates and methods of making and using thereof
EP2103313A1 (fr) * 2008-03-19 2009-09-23 Koninklijke Philips Electronics N.V. Procédé pour la synthèse de sphères creuses
US7924142B2 (en) 2008-06-30 2011-04-12 Kimberly-Clark Worldwide, Inc. Patterned self-warming wipe substrates
US8367427B2 (en) * 2008-08-20 2013-02-05 Baxter International Inc. Methods of processing compositions containing microparticles
US8323685B2 (en) * 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing compositions containing microparticles
US20100047292A1 (en) * 2008-08-20 2010-02-25 Baxter International Inc. Methods of processing microparticles and compositions produced thereby
US8323615B2 (en) * 2008-08-20 2012-12-04 Baxter International Inc. Methods of processing multi-phasic dispersions
CA2750815C (fr) * 2009-02-09 2018-03-13 Swetree Technologies Ab Coques polymeres
US8062555B2 (en) * 2009-04-16 2011-11-22 Rhodia Operations Co-assembly method and co-assembled structures made thereby
WO2011022524A1 (fr) * 2009-08-20 2011-02-24 Florida State University Research Foundation, Inc. Complexes polyélectrolytes biocompatibles et leurs méthodes d’utilisation
CA2799818A1 (fr) 2010-05-24 2011-12-01 University Of Utah Research Foundation Coacervats complexes adhesifs renforces et leurs procedes de production et d'utilisation
US9173971B2 (en) 2010-11-12 2015-11-03 University Of Utah Research Foundation Simple adhesive coacervates and methods of making and using thereof
RU2567320C2 (ru) * 2011-01-28 2015-11-10 Учреждение Российской академии наук Институт теоретической и Экспериментальной биофизики РАН (ИТЭБ РАН) Способ получения подложек с мнонослойным покрытием на основе полиэлектролитных микрокапсул, содержащих биологически активные материалы
EP2747742B1 (fr) * 2011-08-24 2016-01-20 Unilever PLC Particules d'administration d'agent traitant contenant des polysaccharides non-ioniques
ES2555605T3 (es) * 2011-08-24 2016-01-05 Unilever N.V. Partículas de suministro de agente de beneficio que comprenden dextrano
FR2986165B1 (fr) * 2012-01-31 2015-07-24 Capsum Procede de preparation de capsules rigidifiees
CN104736689A (zh) * 2012-10-17 2015-06-24 宝洁公司 非球形小滴
US20150105347A1 (en) * 2012-10-17 2015-04-16 The Procter & Gamble Company Shape-Changing Droplet
US10077324B2 (en) 2013-02-06 2018-09-18 Kci Licensing, Inc. Polymers, preparation and use thereof
FR3013218B1 (fr) * 2013-11-18 2016-07-29 Capsum Composition comprenant des capsules gelifiees stabilisees par un tampon
JP6742297B2 (ja) 2014-07-14 2020-08-19 ユニヴァーシティ オブ ユタ リサーチ ファンデーション その場凝固複合コアセルベートならびにその製造および使用方法
CA3089480A1 (fr) 2018-01-26 2019-08-01 Fluidx Medical Technology, Llc Appareil et procede d'utilisation de coacervats complexes a solidification in situ pour une occlusion vasculaire
CN118599379B (zh) * 2024-07-29 2025-01-03 济南市市政工程建设集团有限公司 一种自修复超疏水纳米防腐涂料及其制备方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047253A1 (fr) * 1998-03-19 1999-09-23 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Fabrication de particules et de coques creuses enduites multicouches par assemblage automatique de multicouches de nanocomposites sur des gabarits colloidaux decomposables
EP0972563A1 (fr) * 1998-07-15 2000-01-19 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Fabrication de particules et coquilles vides revêtues de plusieurs couches par autoassemblage électrostatique de multicouche nanocomposite sur des matrices colloidales décomposables
EP1116516A1 (fr) * 2000-01-13 2001-07-18 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Couchage de particules solides par multicouches polymériques
WO2001064330A1 (fr) * 2000-03-02 2001-09-07 Novosom Ag Nanocapsules a enveloppe de polyelectrolyte

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4640709A (en) * 1984-06-12 1987-02-03 Monsanto Company High concentration encapsulation by interfacial polycondensation
DE59915041D1 (de) * 1998-03-19 2009-07-30 Max Planck Gesellschaft Verfahren zum Aufbringen mehrerer Schichten von Beschichtungssubstanzen auf Templatpartikel
US7101575B2 (en) * 1998-03-19 2006-09-05 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Production of nanocapsules and microcapsules by layer-wise polyelectrolyte self-assembly

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999047253A1 (fr) * 1998-03-19 1999-09-23 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Fabrication de particules et de coques creuses enduites multicouches par assemblage automatique de multicouches de nanocomposites sur des gabarits colloidaux decomposables
EP0972563A1 (fr) * 1998-07-15 2000-01-19 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Fabrication de particules et coquilles vides revêtues de plusieurs couches par autoassemblage électrostatique de multicouche nanocomposite sur des matrices colloidales décomposables
EP1116516A1 (fr) * 2000-01-13 2001-07-18 Max-Planck-Gesellschaft zur Förderung der Wissenschaften e.V. Couchage de particules solides par multicouches polymériques
WO2001064330A1 (fr) * 2000-03-02 2001-09-07 Novosom Ag Nanocapsules a enveloppe de polyelectrolyte

Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002017888A2 (fr) * 2000-08-28 2002-03-07 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Gestion et support de proprietes de liberation de capsules multicouches polyelectrolytiques
WO2002017888A3 (fr) * 2000-08-28 2002-07-25 Max Planck Gesellschaft Gestion et support de proprietes de liberation de capsules multicouches polyelectrolytiques
US7767219B2 (en) 2003-01-31 2010-08-03 Boston Scientific Scimed, Inc. Localized drug delivery using drug-loaded nanocapsules
US8652200B2 (en) 2003-08-11 2014-02-18 Boston Scientific Scimed, Inc. Medical devices comprising drug-loaded capsules for localized drug delivery
US7364585B2 (en) 2003-08-11 2008-04-29 Boston Scientific Scimed, Inc. Medical devices comprising drug-loaded capsules for localized drug delivery
US7538184B2 (en) 2003-08-29 2009-05-26 Louisiana Tech University Foundation Method for controlling stability of nanofabricated polypeptide multilayer films, coatings, and microcapsules
US7534860B2 (en) 2003-08-29 2009-05-19 Louisiana Tech University Foundation Nanofabricated polypeptide multilayer films, coatings, and microcapsules
US7411038B2 (en) 2003-08-29 2008-08-12 Louisiana Tech University Foundation Artificial red blood cells
US7544770B2 (en) 2003-08-29 2009-06-09 Louisiana Tech Foundation, Inc. Multilayer films, coatings, and microcapsules comprising polypeptides
US7550557B2 (en) 2003-08-29 2009-06-23 Louisiana Tech University Foundation, Inc. Multilayer films, coatings, and microcapsules comprising polypeptides
US7348399B2 (en) 2003-08-29 2008-03-25 Louisiana Tech University Foundation, Inc. Nanofabricated polypeptide multilayer films, coatings, and microcapsules
US7893198B2 (en) 2003-08-29 2011-02-22 Louisiana Tech University Foundation, Inc. Multilayer films, coatings, and microcapsules comprising polypeptides
US7321022B2 (en) 2003-08-29 2008-01-22 Louisiana Tech University Foundation, Inc. Method for controlling stability of nanofabricated polypeptide multilayer films, coatings, and microcapsules
US7829119B2 (en) * 2003-10-20 2010-11-09 William Marsh Rice University Method to fabricate microcapsules from polymers and charged nanoparticles
US8119153B2 (en) 2004-08-26 2012-02-21 Boston Scientific Scimed, Inc. Stents with drug eluting coatings
WO2009016091A1 (fr) * 2007-08-01 2009-02-05 Unilever Plc Particules enrobées
US8187583B2 (en) 2009-01-30 2012-05-29 Conopco, Inc. Oil-in-water emulsions

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DE50103245D1 (de) 2004-09-16
WO2002009864A9 (fr) 2002-09-19
US7056554B2 (en) 2006-06-06
CA2417792A1 (fr) 2003-01-30
EP1305109A1 (fr) 2003-05-02
JP2004504931A (ja) 2004-02-19
CA2417792C (fr) 2009-09-08
EP1307282A1 (fr) 2003-05-07
US20040013738A1 (en) 2004-01-22
PT1305109E (pt) 2004-11-30
ES2223914T3 (es) 2005-03-01
US20030175517A1 (en) 2003-09-18
ATE273067T1 (de) 2004-08-15
DK1305109T3 (da) 2004-12-20
WO2002009864A1 (fr) 2002-02-07
EP1305109B1 (fr) 2004-08-11

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